Role of proBNDF and p75NTR in HIV-mediated Axonal/Dendritic Degeneration

proBNDF 和 p75NTR 在 HIV 介导的轴突/树突变性中的作用

基本信息

批准号：
10621350
负责人：
Italo Mocchetti
金额：
$ 54.6万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621350
关键词：
Address Adult Affect Affinity Alleles Animals Apoptotic Applications Grants Area Autopsy Axon Binding Biological Brain Brain Diseases Brain-Derived Neurotrophic Factor Cells Central Nervous System Infections Cerebrospinal Fluid Cognition Data Dendrites Dendritic Spines Diagnosis Enzymes Equilibrium Excision Exhibits Exposure to Functional disorder Golgi Apparatus Grant HIV HIV Envelope Protein gp120 HIV Seropositivity HIV-1 HIV-associated neurocognitive disorder Hippocampus Human Impaired cognition Impairment Investigation Knockout Mice Link Measures Mediating Memory Memory impairment Microfluidics Microtubules Molecular Mus NGFR Protein Nerve Degeneration Nerve Growth Factor Receptors Nervous System Trauma Neurocognitive Deficit Neurodegenerative Disorders Neurologic Dysfunctions Neuronal Injury Neurons Pathologic Play Poison Rattus Receptor Activation Reproducibility Research Role Sampling Severities Signal Transduction Subgroup Synapses Testing Toxic effect Transgenic Mice Transgenic Organisms Vertebral column Viral Proteins antagonist antiretroviral therapy behavioral study brain-derived neurotrophic factor precursor env Gene Products experimental study induced pluripotent stem cell nerve stem cell neurocognitive disorder neuronal survival neuronal transport neurotoxic neurotoxicity neurotrophic factor novel postsynaptic presynaptic prevent receptor transcriptional coactivator p75

项目摘要

Abstract Human immunodeficiency virus-1 (HIV) infection of the central nervous system damages synapses and promotes neuronal injury that culminates in HIV-associated neurocognitive disorders (HAND). How HIV damages synapses is still under investigation. Viral proteins, including the envelope protein gp120, have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear. The balance between neuronal survival and damage is predominantly governed by neurotrophic factors, and in particular, brain-derived neurotrophic factor (BDNF) and its precursor proBDNF. proBDNF, when bound to the neurotrophin receptor p75 (p75NTR) activates a pro-apoptotic signal. We have shown that brains of HAND subjects, as well as neurons exposed to gp120, exhibit a significant increase of proBDNF, which correlates with a decreased expression of furin, a key enzyme in the processing of proBDNF. The removal of one allele of p75NTR, the receptor for proBDNF, rescues the loss of synapses seen in gp120 transgenic mice. Therefore, we hypothesize that HIV damages synapses through the ability of gp120 to increase proBDNF and therefore activating p75NTR. This is an important line of research because synaptic degeneration dysfunction has been linked to numerous neurodegenerative diseases but only preliminarily to HAND. The molecular and cellular mechanisms of how gp120 causes impairs/damages synapses remain under investigation. This application proposes a comprehensive set of experiments to test the main hypothesis. In particular (AIM 1), we will test the hypothesis that gp120 reduces furin levels by directly binding to this endoprotease. We will utilize (AIM 2) p75NTR-/- neurons and p75NTR antagonists to examine the mechanisms and signaling of gp120 neurotoxicity. We will perform behavioral studies for memory function (AIM 3) in gp120 transgenic (gp120tg) mice intercrossed with p75NTR null mice to investigate whether the removal of one allele for p75NTR rescues the memory impairment observed in gp120tg mice. Finally, (AIM 4) we will use human samples including the cerebrospinal fluid (CSF) to determine whether the levels of proBDNF are altered in different subgroups of HAND subjects. Levels of gp120 will also be measured in the CSF. These experiments might establish a correlation between levels of proBDNF, gp120 and neurocognitive impairment. We expect to provide new significant data on the role of p75NTR in HIV-mediated synaptic simplification.

抽象的人类免疫缺陷病毒 1 (HIV) 感染中枢神经系统会损害突触和促进神经元损伤，最终导致 HIV 相关神经认知障碍 (HAND)。艾滋病毒如何突触损伤仍在调查中。病毒蛋白，包括包膜蛋白 gp120，具有成为解释艾滋病毒介导的神经毒性的主要候选者，尽管其机制仍不清楚。神经元存活和损伤之间的平衡主要由神经营养因子控制，并且特别是脑源性神经营养因子（BDNF）及其前体 proBDNF。 proBDNF，当结合到神经营养蛋白受体 p75 (p75NTR) 激活促凋亡信号。我们已经证明了 HAND 的大脑受试者以及暴露于 gp120 的神经元表现出 proBDNF 的显着增加，这与弗林蛋白酶（proBDNF 加工中的关键酶）的表达减少。去除一个等位基因 p75NTR（proBDNF 受体）的 p75NTR 可以挽救 gp120 转基因小鼠中出现的突触损失。因此，我们假设 HIV 通过 gp120 增加的能力来损害突触 proBDNF 从而激活 p75NTR。这是一个重要的研究方向，因为突触退行性功能障碍与许多神经退行性疾病有关，但只是初步相关。手。 gp120 如何导致突触损伤/损伤的分子和细胞机制仍然存在正在调查中。该应用程序提出了一套全面的实验来检验主要假设。特别是（AIM 1），我们将测试 gp120 通过直接结合到此来降低弗林蛋白酶水平的假设内切蛋白酶。我们将利用 (AIM 2) p75NTR-/- 神经元和 p75NTR 拮抗剂来检查其机制和 gp120 神经毒性的信号传导。我们将在 gp120 中进行记忆功能 (AIM 3) 的行为研究转基因 (gp120tg) 小鼠与 p75NTR 缺失小鼠杂交，以研究是否去除了一个等位基因 p75NTR 可以挽救 gp120tg 小鼠中观察到的记忆障碍。最后，（AIM 4）我们将使用人类包括脑脊液 (CSF) 在内的样本，以确定 proBDNF 的水平是否在 HAND 科目的不同亚组。脑脊液中 gp120 的水平也将被测量。这些实验可能会在 proBDNF、gp120 水平和神经认知障碍之间建立相关性。我们期望提供关于 p75NTR 在 HIV 介导的突触简化中的作用的新的重要数据。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synaptic dysfunction in human immunodeficiency virus type-1-positive subjects: inflammation or impaired neuronal plasticity?

人类免疫缺陷病毒 1 型阳性受试者的突触功能障碍：炎症或神经元可塑性受损？

DOI：
发表时间：
2013-05
期刊：
影响因子：
11.1
作者：
Avdoshina, V;Bachis, A;Mocchetti, I
通讯作者：
Mocchetti, I

HIV-1 Tg 大鼠黑质酪氨酸羟化酶免疫反应性与年龄相关的降低和小胶质细胞形态的区域特异性变化。

DOI：
发表时间：
2019-10
期刊：
影响因子：
3.7
作者：
Goulding, David R;Kraft, Andrew;Mouton, Peter R;McPherson, Christopher A;Avdoshina, Valeria;Mocchetti, Italo;Harry, G Jean
通讯作者：
Harry, G Jean

Neuronal apoptosis induced by morphine withdrawal is mediated by the p75 neurotrophin receptor.

吗啡戒断诱导的神经细胞凋亡是由 p75 神经营养蛋白受体介导的。